I. Organometallic Enantiomeric Scaffolding: Total Synthesis of(-)-Adaline and (-)-Adalinine Using a Key 5-Oxo-PyridinylMolybdenum Scaffold and Featuring a SemipinacolRearrangment/1,5-"Michael-like" Sequence.II. Exchange Reactions of 1-Alkoxy and 1-Sulfonyloxy 3-AllylMolybdenum Complexes Pubblico
Coombs, Thomas Charles (2008)
Abstract
A short, practical route to a versatile 5-oxo-(-2,3,4)-allylmolybdenum pyridinyl scaffold has been developed using the aza-Achmatowicz rearrangement. This route features a one-pot rearrangement/metalation protocol, eliminating the need for purification of sensitive intermediates, and enabling the easy synthesis of multi-gram quantities of the scaffold in a timely manner. The protocol has been extended to chiral non-racemic substrates, providing improved access to both enantiomers of this complex in high enantiomeric excesses. A new variant of the semipinacol rearrangement was investigated utilizing allylic alcohols available in three steps from 5-oxo-(-2,3,4)-allylmolybdenum pyranyl and pyridinyl organometallic enantiomeric scaffolds. The protic acid-induced semipinacol rearrangement itself occured with complete diastereoselectivity under mild conditions and required a full equivalent of HCl. Off-ring stereocenters were efficiently generated using electrophilic halogen sources to initiate the rearrangement. The major diastereomer in each case resulted from addition to the alkene syn to the TpMo(CO)2 fragment, suggesting participation of the metal in this rearrangment. Solvent choice was especially important in these reactions to achieve synthetically-useful diastereoselectivities at the off-ring site. Asymmetric syntheses of (-)-adaline and (-)-adalinine were carried out using the enantiomerically-enriched 5-oxo-(-2,3,4)-allylmolybdenum pyridinyl complex. The synthesis of (-)-adalinine highlighted the utility of the semipinacol rearrangement for the stereocontrolled construction of quaternary centers, and also employed an oxidative demetalation protocol previously developed by the Liebeskind group to install the lactam carbonyl found in the natural product. The synthesis of (-)-adaline showcased the power of coupling the semipinacol rearrangement and 1,5-Michael-like reaction to access quaternary center-bearing bicyclic compounds. A family of related 1-alkoxy and 1-sulfonyloxy-3-allylmolybdenum complexes were shown to undergo a series of exchange reactions with external amines and alcohol nucleophiles. Alkoxy complexes reacted directly with amines, but required the participation of a Lewis acid catalyst to undergo substitution with alcohols. Sulfonyloxy complexes reacted directly with both amines and alcohols in the absence of any catalyst. In all cases, optically-active starting materials racemized when subjected to exchange conditions, suggesting that this family of reactions proceeds via carbene intermediates. Additionally, 5-oxo-pyranyl complex 1.6 was found to undergo rapid ring-opening amination reactions with both primary and secondary amines, suffering only small loss in enantiomeric purity.
Table of Contents
Chapter One. Development of an Improved Route to a Key 5-Oxo-Pyridinyl Organometallic Enantiomeric Scaffold
Introduction
Development of Organometallic Enantiomeric Scaffolds
The Aza-Achmatowicz Reaction: Background and Application
Results and Discussion
Experimental Section
General Methods
Chapter Two. Semipinacol Rearrangement of TpMo(CO)2-Based Allylic Alcohols
Background
Introduction
Results and Discussion
Experimental Section
Crystal Structure Analyses
Chapter Three. Total Synthesis of (-)-Adaline and (-)-Adalinine
Background
Early Work on Homotropanes: Pseudopelletierine
Isolation and Biosynthetic Studies: (+)-Euphococcinine, (-)-Adaline, and (-)-Adalinine
Racemic Approaches to Adaline and Euphococcinine
Asymmetric Syntheses of (-)-Adaline and (+)-Euphococcinine
Racemic Approaches to Adalinine
Asymmetric Syntheses of (-)-Adaline
Introduction
Results and Discussion
Synthesis of Common Intermediate
Synthesis of (-)-Adaline
Model 1,5-Michael Study
Continuing Towards (-)-Adaline
Synthesis of (-)-Adalinine
Experimental Section
Crystal Structure Analysis
Chapter Four. Novel Substitutions of 1-Alkoxy- and 1-Sulfonyloxy-η3-Allylmolybdenum Complexes: Mechanism, Scope, and Limitations
Introduction
Results and Discussion
Substrate Synthesis
Direct Exchange of Alkoxy Substitutents with Amines
Lewis Acid-Catalyzed Exchange of Alkoxy Substituents with Alcohols
Direct Exchange of Sulfonate Esters with Amines and Alcohols
Accessing Chiral, Non-racemic Complexes
Exchange Reactions with Chiral, Non-racemic Substrates
Mechanistic Rationale
Ring-opening Amination of TpMo(CO)2 5-Oxo-pyranyl Complex
Experimental Section
Crystal Structure Analyses
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